Surfaces of medical devices that are in direct contact with biological materials, such as tissues, blood and blood products, have been treated with surface modifying agents in order to make the contacting surfaces compatible with these types of sensitive biological materials. Sulfated polysaccharides have been used in a variety of applications to make biocompatible medical surfaces. For example, the blood contacting surfaces of devices such as blood oxygenators, blood pumps, catheters, or connection tubes and tubing may be treated with biologically active polysaccharides, particularly heparin or heparin derivatives, to make the surfaces of such devices nonthrombogenic and thus prevent clotting or clot formation related to surface contact with blood or blood products.
Several methods for specifically attaching or binding heparin or heparin derivatives to substrate surfaces have been reported. U.S. Pat. Nos. 4,613,665 and 4,810,784 report a process to attach heparin to different types of substrates. The reported process degrades a polysaccharide antithrombogenic agent, such as heparin, with nitrous acid to give fragments which react with primary amino groups on the substrate's surface to form intermediate Schiffs base conjugates. Reduction of the intermediate conjugates then covalently binds the fragments to the support.
In addition, U.S. Pat. No. 4,565,740 reports a substrate modified to include degraded heparin fragments where the substrate is initially treated with a polyamine and a dialdehyde crosslinker, then treated with dextran sulfate, further treated with a polyamine and finally treated with degraded heparin and sodium cyanoborohydride to chemically bind the heparin fragments to the polyamine. Similarly, U.S. Pat. No. 5,049,403 reports a substrate modified to include degraded heparin fragments where the substrate is initially treated with a polyamine that is crosslinked with crotonaldehyde.
Further, U.S. Pat. No. 4,326,532 reports a layered substrate coated with chitosan that reacts with an antithrombotic agent such as heparin. Specifically, heparin is condensed with a layer of chitosan that is initially applied to an acid oxidized or plasma etched hydrophobic substrate and, if needed, the condensed heparin is then reduced using sodium cyanoborohydride.
Alternative methods of modifying surfaces with activated heparin have also been reported. For example, U.S. Pat. Nos. 4,720,512 and 4,786,556 report activating heparin with sodium periodate, reacting the periodate-activated heparin with an amine-containing material to form a conjugate and then reducing the conjugate using sodium cyanoborohydride.
Besides various heparin activation and chemical bonding methods, other processes have been used to fix or attach heparin to substrates without actually chemically bonding heparin to the substrate. For example, U.S. Pat. No. 4,871,357 reports an ionic binding of heparin to surfaces using quaternary ammonium salts. Subsequent irradiation of ionically bound heparin using quaternary ammonium salts has been reported to covalently bond heparin to the surface. See, e.g., International Application No. PCT/US92/07661 published Apr. 1, 1993.
In spite of the many approaches to modify surfaces with biologically useful agents, a need exists for an efficient, effective process to prepare such modified surfaces which uses reagents which are easy to handle and are not toxic or hazardous to use. Polysaccharides are particularly difficult to work with because these polymers are generally not soluble in organic solvents and thus are not readily used with many common reaction methodologies. Thus, a preferred process would be carried out in an aqueous system.
Furthermore, the biological activity of active polysaccharides may be very sensitive to processing conditions. A desirable process would allow binding biologically active polysaccharides, such as heparin, to surfaces without degrading or otherwise altering the biological activity of the active polysaccharide when it is used to modify the surface of a substrate. A need exists for a process which may be adapted for use with many different types of active polysaccharides and substrates and which does not result in degradation or alteration of the biological activity of the active polysaccharide.